Complete and Durable Response to Nivolumab in Recurrent Poorly Differentiated Pancreatic Neuroendocrine Carcinoma with High Tumor Mutational Burden

Kang, Nai‐Wen; Tan, Kien Thiam; Li, Chien‐Feng; Kuo, Yu‐Hsuan

doi:10.3390/curroncol28060388

Cited by 5 publications

(4 citation statements)

References 38 publications

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“…Therefore, it can be concluded from these findings that the main driver genes are those with high mutational frequency in NET. In addition, NEC may have a higher mutational burden than NET, which is consistent with the observations in other benign and malignant tumors [29]. Although the high-frequency driver genes have been largely consistent in the previous studies, heterogeneity still existed among different studies.…”

Section: Endocrine Journal Advance Publicationsupporting

confidence: 86%

“…A whole-genome study on pancreatic NETs showed that somatic mutations, including point mutations and gene fusions, are commonly found in genes involved in four major pathways: chromatin remodeling, DNA damage repair, activation of mTOR signaling, including previously undescribed EWSR1 gene fusions, and telomere maintenance [32]. In contrast, abnormally regulated Notch signaling [29], Wnt signaling [30], and RAS/RAF/MEK/ERK signaling [33] are the main pathways in rectal NETs, although aberrant mTOR signaling is also involved [34]. Therefore, NETs in different organs exhibit common but distinct aberrant signaling pathways, with enormous heterogeneity.…”

Section: Endocrine Journal Advance Publicationmentioning

confidence: 99%

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The genetic alterations of rectal neuroendocrine tumor and indications for therapy and prognosis: a systematic review

Liu

Han

et al. 2023

Endocr J

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Neuroendocrine tumors (NETs) are a type of rare tumor that can occur at multiple organs. Rectal NETs are the most common NETs in gastrointestinal tract. Due to the rarity of rectal NETs in rectal cancer, the molecular features and the correlation with patient therapeutic response and prognosis have not been investigated in detail. In this review, we focused on the molecular features, potential therapeutic targets and prognosis of rectal NETs. By summarizing the relevant studies, we established the mutational landscape of rectal NETs and identified a series of large fragment variations. Driver genes including TP53, APC, KRAS, BRAF, RB1, CDKN2A and PTEN were found as the top mutated genes. Large fragment alterations mainly involved known driver genes, including APC, TP53, CCNE1, MYC, TERT, RB1 and ATM. Germline mutations of APC, MUTYH, MSH6, MLH1 and MSH2 associated with Lynch syndrome or FAP were also found in rectal NETs. The BRAF-V600E mutation was reported as an actionable target in rectal NETs, and the combined BRAF/MEK inhibitors were found to be effective targeting BRAF-V600E in advanced or metastatic NETs. The known prognostic risk factors of rectal adenocarcinoma, including a series of demographic and clinicopathological factors were also prognostic factors for rectal NETs. Furthermore, three types of markers, including genetic alterations, protein expression levels and methylation, were also suggested as prognostic factors for rectal NETs. In summary, we established the landscape of mutations and large-fragment alterations of rectal NETs, and identified potential therapeutic targets and a series of prognostic factors. Future studies may focus on the optimization of therapeutic strategies based on potential actionable biomarkers.

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Section: Endocrine Journal Advance Publicationsupporting

confidence: 86%

Section: Endocrine Journal Advance Publicationmentioning

confidence: 99%

The genetic alterations of rectal neuroendocrine tumor and indications for therapy and prognosis: a systematic review

Liu

Han

et al. 2023

Endocr J

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“…Tumour MSI-H/dMMR status as well as high-TMB (≥10 mut/Mb) are known predictive biomarkers of response to CPIs, leading to tissue agnostic FDA approvals of CPIs for progressing solid tumours [44][45][46]. In terms of PDNECs specifically, beyond our clinical trial, there are anecdotal reports of response to CPIs in high-TMB and/or MSI-H EP-PDNECs [47][48][49][50][51][52]. A subset of treated tumours (N = 28) in this study were tested for MSI and dMMR, and no tumours were MSI-H/dMMR.…”

Section: Discussionmentioning

confidence: 99%

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

et al. 2023

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BACKGROUND:To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarkerunselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. Primary endpoint: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

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“…Studies of the human microbiome and its impact on the efficacy of immunotherapy on NETs needs further investigation. Although ICI therapy is technically effective in treating tumors with high-TMB 68 , particularly with NECs 135 , the cut-offs associated with TMBs have thus far been inconsistent with the predictability of response to ICI therapy, and on some other cancers, ICI therapy has not resulted in improved ORR among patients with high-TMB as compared to patients with low-TMB 64 . The current FDA-approved indication for the use of pembrolizumab on the basis of high-TMB may be too broad and further tailoring of indications based on other factors such as environmental carcinogen exposure are being suggested for consideration 136 .…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors

Gubbi

Vijayvergia

et al. 2022

Horm Metab Res

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Neuroendocrine tumors (NETs) occur in various regions of the body and present with complex clinical and biochemical phenotypes. The molecular underpinnings that give rise to such varied manifestations have not been completely deciphered. The management of neuroendocrine tumors (NETs) involves surgery, locoregional therapy, and/or systemic therapy. Several forms of systemic therapy, including platinum-based chemotherapy, temozolomide/capecitabine, tyrosine kinase inhibitors, mTOR inhibitors, and peptide receptor radionuclide therapy have been extensively studied and implemented in the treatment of NETs. However, the potential of immune checkpoint inhibitor (ICI) therapy as an option in the management of NETs has only recently garnered attention. Till date, it is not clear whether ICI therapy holds any distinctive advantage in terms of efficacy or safety when compared to other available systemic therapies for NETs. Identifying the characteristics of NETs that would make them (better) respond to ICIs has been challenging. This review provides a summary of the current evidence on the value of ICI therapy in the management of ICIs and discusses the potential areas for future research.

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Complete and Durable Response to Nivolumab in Recurrent Poorly Differentiated Pancreatic Neuroendocrine Carcinoma with High Tumor Mutational Burden

Cited by 5 publications

References 38 publications

The genetic alterations of rectal neuroendocrine tumor and indications for therapy and prognosis: a systematic review

The genetic alterations of rectal neuroendocrine tumor and indications for therapy and prognosis: a systematic review

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas

Immune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors

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